Characterization of Immature Myofibroblasts of Stellate Cell or Mesenchymal Cell Origin in D-Galactosamine-Induced Liver Injury in Rats

2020 ◽  
pp. 030098582096309
Author(s):  
Nahid Rahman ◽  
Mizuki Kuramochi ◽  
Takeshi Izawa ◽  
Mitsuru Kuwamura ◽  
Jyoji Yamate
Keyword(s):  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Mesenchymal Cell ◽  
Mesenchymal Cells ◽  
Cytoskeletal Proteins ◽  
Related Factors ◽  
Tnf Α ◽  
Focal Hepatic Lesions ◽  
Hepatic Lesions ◽  
Hepatocyte Necrosis

Lesions of D-galactosamine (D-GalN)-induced hepatotoxicity resemble those of human acute viral hepatitis. This study investigated hepatic mesenchymal cells including hepatic stellate cells (HSCs) and myofibroblasts in D-GalN-induced hepatotoxicity. Rats, injected with D-GalN (800 mg/kg body weight, once, intraperitoneally) were examined on post single injection (PSI) at 8 hours and days 1 to 5. Lesions consisting of hepatocyte necrosis and reparative fibrosis were present diffusely or focally within the hepatic lobules on PSI days 1 and 2, and then the injury recovered on PSI days 3 and 5. Myofibroblasts expressing vimentin, desmin, and α-smooth muscle actin (α-SMA) were present in the lesions. Double immunofluorescence showed that myofibroblasts reacted simultaneously to vimentin/α-SMA, desmin/α-SMA, and desmin/vimentin; furthermore, myofibroblasts reacting to vimentin, desmin, and α-SMA also co-expressed glial fibrillary acidic protein (GFAP), a marker of HSCs. Additionally, GFAP-expressing myofibroblasts reacted to nestin and A3 (both are markers of immature mesenchymal cells). Cells reacting to Thy-1, a marker for immature mesenchymal cells, also appeared in fibrotic lesions. In agreement with the myofibroblastic appearance, mRNAs of fibrosis-related factors (TGF-β1, PDGF-β, TNF-α, Timp2, and Mmp2) increased mainly on PSI days 1 and 2. Myofibroblasts with expression of various cytoskeletal proteins were present in diffuse or focal hepatic lesions, and they might be derived partly from immature HSCs and from immature mesenchymal cells.

Characterization of Macrophages and Myofibroblasts Appearing in Dibutyltin Dichloride–Induced Rat Pancreatic Fibrosis

2020 ◽  
Vol 48 (3) ◽  
pp. 509-523
Author(s):  
Ai Hashimoto ◽  
Mohammad Rabiul Karim ◽  
Mizuki Kuramochi ◽  
Takeshi Izawa ◽  
Mitsuru Kuwamura ◽  
...  
Keyword(s):  
Smooth Muscle Actin ◽  
Mesenchymal Cells ◽  
Cytoskeletal Proteins ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Dibutyltin Dichloride ◽  
Chemically Induced ◽  
M1 Macrophage ◽  
Reliable Marker

Macrophages and myofibroblasts are important in fibrogenesis. The cellular characteristics in pancreatic fibrosis remain to be investigated. Pancreatic fibrosis was induced in F344 rats by a single intravenous injection of dibutyltin dichloride. Histopathologically, the induced pancreatic fibrosis was divided into 3 grades (1+, 2+, and 3+), based on collagen deposition. Immunohistochemically, CD68-expressing M1 macrophages increased with grade and CD163-expressing M2 macrophages also increased later than M1 macrophage appearance. Double immunofluorescence showed that there were macrophages coexpressing CD68 and CD163, suggesting a possible shift from M1 to M2 types; similarly, increased major histocompatibility complex class II- and CD204-expressing macrophages were polarized toward M1 and M2 types, respectively. These findings indicated the participation of M1- and M2-polarized macrophages. Mesenchymal cells staining positive for vimentin, desmin, and α-smooth muscle actin (α-SMA) increased with grade. There were mesenchymal cells coexpressing vimentin/α-SMA, desmin/α-SMA, and glial fibrillary acidic protein (GFAP)/α-SMA; Thy-1-expressing immature mesenchymal cells also increased in fibrotic lesions. Because α-SMA expression is a reliable marker for myofibroblasts, α-SMA-expressing pancreatic myofibroblasts might be originated from GFAP-expressing pancreatic stellate cells or Thy-1-expressing immature mesenchymal cells; the myofibroblasts could simultaneously express cytoskeletal proteins such as vimentin and desmin. The present findings would provide useful information for analyses based on features of macrophages and myofibroblasts in chemically induced pancreatic fibrosis.

Bee Venom Inhibits Hepatic Fibrosis Through Suppression of Pro-Fibrogenic Cytokine Expression

2010 ◽  
Vol 38 (05) ◽  
pp. 921-935 ◽  
Author(s):  
Soo-Jung Kim ◽  
Ji-Hyun Park ◽  
Kyung-Hyun Kim ◽  
Woo-Ram Lee ◽  
Young-Chae Chang ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Inflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Smooth Muscle Actin ◽  
Bee Venom ◽  
Tnf Α ◽  
Hepatocyte Necrosis ◽  
Tgf Β1 ◽  
Pro Inflammatory Cytokines

Bee venom (BV) has a long tradition of use for the control of pain and inflammation in various chronic diseases. Carbon tetrachloride ( CCl4 ) is known to induce hepatotoxicity after being metabolized to the highly reactive trichloromethyl free radical and its peroxy radical. The purpose of the current study was to examine whether BV regulates the pro-inflammation and fibrosis related genes against a mouse model of hepatic fibrosis induced by CCl4 and ethanol-treated hepatocytes (ETH). Test mice were administered with CCl4 (2 ml/mg) and hepatocytes were treated with 25 mM ethanol. BV was added to the final concentration of 0.05–0.5 mg/kg and 1–100 ng/ml for in vivo and in vitro testing, respectively. Fibrotic livers and ETH were used for the measurement of hepatocyte necrosis, pro-inflammatory cytokines and fibrogenic genes. BV suppressed CCl4 -induced hepatocyte necrosis markers of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). It also inhibited the secretion of interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Moreover, BV inhibited CCl4 -induced expression of transforming growth factor (TGF)-β1, α-smooth muscle actin (SMA) and fibronectin. Similarly, ETH exhibited significant suppression of IL-1β, TNF-α, TGF-β1 and fibronectin when cultured with BV. These results suggest that BV possesses anti-fibrogenic properties that are mediated by the suppression of pro-inflammatory cytokines and fibrogenic gene expression. BV has substantial therapeutic potential for the treatment of fibrotic diseases.

scholarly journals Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

2015 ◽  
Vol 308 (5) ◽  
pp. G403-G415 ◽  
Author(s):  
Martin J. J. Ronis ◽  
Kelly E. Mercer ◽  
Brenda Gannon ◽  
Bridgette Engi ◽  
Piotr Zimniak ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Growth Factor ◽  
Liver Injury ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Matrix Remodeling ◽  
Double Knockout ◽  
Tnf Α

To test the significance of lipid peroxidation in the development of alcoholic liver injury, an ethanol (EtOH) liquid diet was fed to male 129/SvJ mice (wild-type, WT) and glutathione S-transferase A4–4-null (GSTA4−/−) mice for 40 days. GSTA4−/− mice were crossed with peroxisome proliferator-activated receptor-α-null mice (PPAR-α−/−), and the effects of EtOH in the resulting double knockout (dKO) mice were compared with the other strains. EtOH increased lipid peroxidation in all except WT mice ( P < 0.05). Increased steatosis and mRNA expression of the inflammatory markers CXCL2, tumor necrosis factor-α (TNF-α), and α-smooth muscle actin (α-SMA) were observed in EtOH GSTA4−/− compared with EtOH WT mice ( P < 0.05). EtOH PPAR-α−/− mice had increased steatosis, serum alanine aminotransferase (ALT), and hepatic CD3+ T cell populations and elevated mRNA encoding CD14, CXCL2, TNF-α, IL-6, CD138, transforming growth factor-β, platelet-derived growth factor receptor-β (PDGFR-β), matrix metalloproteinase (MMP)-9, MMP-13, α-SMA, and collagen type 1 compared with EtOH WT mice. EtOH-fed dKO mice displayed elevation of periportal hepatic 4-hydroxynonenal adducts and serum antibodies against malondialdehyde adducts compared with EtOH feeding of GSTA4−/−, PPAR-α−/−, and WT mice ( P < 0.05). ALT was higher in EtOH dKO mice compared with all other groups ( P < 0.001). EtOH-fed dKO mice displayed elevated mRNAs for TNF-α and CD14, histological evidence of fibrosis, and increased PDGFR, MMP-9, and MMP-13 mRNAs compared with the EtOH GSTA4−/− or EtOH PPAR-α−/− genotype ( P < 0.05). These findings demonstrate the central role lipid peroxidation plays in mediating progression of alcohol-induced necroinflammatory liver injury, stellate cell activation, matrix remodeling, and fibrosis.

Focal hepatic lesions: Differential diagnosis with MRI

1993 ◽  
Vol 29 (4) ◽  
pp. 747
Author(s):  
Jong Sool Ihm ◽  
Kwi Ae Park ◽  
Woo Hyun Ahn ◽  
Bong Gi Kim ◽  
Han Yong Choi
Keyword(s):  
Differential Diagnosis ◽  
Focal Hepatic Lesions ◽  
Hepatic Lesions

Expression and Significance of Th17 Cells and Related Factors in Patients with Autoimmune Hepatitis

2019 ◽  
Vol 22 (4) ◽  
pp. 232-237 ◽  
Author(s):  
Jihong An
Keyword(s):  
Autoimmune Hepatitis ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Treg Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Serum Total Bilirubin ◽  
Study Group ◽  
Related Factors ◽  
Tnf Α

Objective: This study aims to investigate the expression and clinical significance of Th17 cells and related factors in peripheral blood of patients with Autoimmune Hepatitis (AIH). Methods: A retrospective selection of 100 patients with AIH were included as a study group, and 100 healthy volunteers in the outpatient clinic were selected as the control group. The levels of IL- 17, IL-6, IL-21 and TNF-α in peripheral blood of all subjects were detected by enzyme-linked immunosorbent assay and the frequency of Th17 cells and Treg cells was detected by flow cytometry. Results: Results showed that the study group had higher levels of serum total bilirubin (TBil), alkaline phosphatase (ALP), γ -glutamyltranspeptidase (γ-GT), immunoglobulin G (IgG), immunoglobulin M (IgM), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) than the control group, as well as higher levels of IL-17, IL-6, IL-21 and TNF-α in serum. The frequency of Th17 cells in peripheral blood was higher in the study group, while the frequency of Treg cells was lower. Also, serum IL-17, TNF-α levels and Th17 cells frequency were positively correlated with ALT and AST, whereas Treg cells frequency were negatively correlated with ALT and AST levels. Conclusion: Our finding demonstrates that Th17 cell frequency and their related factors IL-17 and TNF-α, are associated with liver damage, which might be used to monitor AIH disease severity.

scholarly journals HGF/c-Met Inhibition as Adjuvant Therapy Improves Outcomes in an Orthotopic Mouse Model of Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2763
Author(s):  
Tony C. Y. Pang ◽  
Zhihong Xu ◽  
Alpha Raj Mekapogu ◽  
Srinivasa Pothula ◽  
Therese Becker ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Progression ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Primary Tumour ◽  
Human Pancreatic Cancer ◽  
Pancreatic Stellate Cell ◽  
Orthotopic Mouse Model ◽  
Pancreatic Cancer Cells ◽  
Angiogenic Effect

Background: Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)−PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated existence of circulating PSCs (cPSCs) as a mediator of metastatic PC. Methods: Two orthotopic PC mouse models, produced by implantation of a mixture of luciferase-tagged human pancreatic cancer cells (AsPC-1), and human PSCs were used. Model 1 mice underwent distal pancreatectomy 3-weeks post-implantation (n = 62). One-week post-resection, mice were randomised to four treatments of 8 weeks: (i) IgG, (ii) gemcitabine (G), (iii) HGF/c-MET inhibition (HiCi) and (iv) HiCi + G. Tumour burden was assessed longitudinally by bioluminescence. Circulating tumour cells and cPSCs were enriched by filtration. Tumours of Model 2 mice progressed for 8 weeks prior to the collection of primary tumour, metastases and blood for single-cell RNA-sequencing (scRNA-seq). Results: HiCi treatments: (1) reduced both the risk and rate of disease progression after resection; (2) demonstrated an anti-angiogenic effect on immunohistochemistry; (3) reduced cPSC counts. cPSCs were identified using immunocytochemistry (α-smooth muscle actin+, pan-cytokeratin−, CD45−), and by specific PSC markers. scRNA-seq confirmed the existence of cPSCs and identified potential genes associated with development into cPSCs. Conclusions: This study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition for PC and provides the first confirmation of the existence of circulating PSCs.

MR imaging with i.v. superparamagnetic iron oxide: efficacy in the detection of focal hepatic lesions.

1993 ◽  
Vol 161 (6) ◽  
pp. 1191-1198 ◽  
Author(s):  
T C Winter ◽  
P C Freeny ◽  
H V Nghiem ◽  
L A Mack ◽  
R M Patten ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Mr Imaging ◽  
Superparamagnetic Iron Oxide ◽  
Focal Hepatic Lesions ◽  
Hepatic Lesions

Sparing of Fatty Infiltration Around Focal Hepatic Lesions in Patients with Hepatic Steatosis: Sonographic Appearance with CT and MRI Correlation

2008 ◽  
Vol 190 (4) ◽  
pp. 1018-1027 ◽  
Author(s):  
Kyoung Won Kim ◽  
Min Ju Kim ◽  
Seung Soo Lee ◽  
Hyoung Jung Kim ◽  
Yong Moon Shin ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Fatty Infiltration ◽  
Sonographic Appearance ◽  
Focal Hepatic Lesions ◽  
Hepatic Lesions ◽  
Ct And Mri

Acetylcholinesterase (AChE) and pseudocholinesterase (BuChE) activity distribution pattern in early developing chick limbs

Development ◽  
1985 ◽  
Vol 86 (1) ◽  
pp. 89-108
Author(s):  
Carla Falugi ◽  
Margherita Raineri
Keyword(s):  
Plasma Membrane ◽  
Basal Lamina ◽  
Ache Activity ◽  
Quantitative Methods ◽  
Mesenchymal Cell ◽  
Mesenchymal Cells ◽  
Regional Localization ◽  
Stage Of Development ◽  
Limb Morphogenesis ◽  
Cell Processes

The distribution of acetylcholinesterase (AChE) and pseudocholinesterase (BuChE) activities was studied by histochemical, quantitative and electrophoretical methods during the early development of chick limbs, from stage 16 to stage 32 H.H. (Hamburger & Hamilton, 1951). By quantitative methods, true AChE activity was found, and increased about threefold during the developmental period, together with a smaller amount of BuChE which increased more rapidly in comparison with the AChE activity from stage 25 to 32 H.H. Cholinesterase activity was histochemically localized mainly in interacting tissues, such as the ectoderm (including the apical ectodermal ridge) and the underlying mesenchyme. True AChE was histochemically localized around the nuclei and on the plasma membrane of ectodermal (including AER) and mesenchymal cells, and at the plasma membrane of mesenchymal cell processes reaching the basal lamina between the ectoderm and the mesenchyme. AChE together with BuChE activity was found in the basal lamina between the ectoderm and the mesenchyme, in underlying mesenchymal cells and in deeper mesenchymal cells, especially during their transformation into unexpressed chondrocytes. During limb morphogenesis, the cellular and regional localization of the enzyme activities showed variations depending on the stage of development and on the occurrence of interactions. The possibility of morphogenetic functions of the enzyme is discussed.

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